Discovery of Novel d-(+)-Biotin-Conjugated Resorcinol Dibenzyl Ether-Based PD-L1 Inhibitors for Targeted Cancer Immunotherapy

摘要

Inthis work, we rationally designed, synthesized, and evaluateda series of novel d-(+)-biotin-conjugated PD-L1 inhibitorsfor targeted cancer therapy. Among them, SWS1 exhibitedthe highest anti-PD-1/PD-L1 activity with an IC50 of 1.8nM. In addition, SWS1 dose-dependently promoted tumorcell death in a HepG2/Jurkat cell co-culture model. Importantly, SWS1 displayed high antitumor efficacy in a B16-F10 mousemodel with tumor growth inhibition of 66.1%, which was better thanthat of P18 (44.3%). Furthermore, SWS1 exertedantitumor effects by increasing the number of tumor-infiltrating lymphocytesand reducing the expression of PD-L1 in tumor tissues. Moreover, tissuedistribution studies revealed a substantial accumulation of SWS1 in tumors (404.1 ng/mL). Lastly, the safety profilesof SWS1 were better (e.g., less immune-mediated colitis)than those of P18, indicating the advantages of biotin-enabledtumor targeting capability. Taken together, our results suggest thatthese novel tumor-targeted PD-L1 inhibitors are worthy of furtherinvestigation as potential anticancer agents for targeted cancer immunotherapy

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